Turalio risk evaluation and mitigation strategy for treatment of tenosynovial giant cell tumor: framework and experience

Risk Evaluation andMitigation Strategies & its components

Risk minimization measures aim to optimize the safe and effective use of a medicinal product throughout its life cycle [1]. When a drug is approved, the market authorization holder (MAH) is responsible for implementing risk minimization measures for the product as part of their routine pharmacovigilance activities. The majority of safety concerns associated with the drug utilization are addressed by routine risk minimization measures. One of the commonly used routine risk minimization measures involves the use of the legal, or prescription status of the product. An example of this would be to sell a product under prescription status instead of as an over-the-counter medication. By doing so, access to the medication is restricted to those who have visited a physician and for whom the medication is deemed appropriate. The patient would then be subsequently prescribed the specific medication. This differs significantly from over-the-counter medications for which medical oversight is not present [1,2].

Other routine risk minimization measures involve the use of the prescribing information (USPI), the package insert, the pack size and design and the labeling [1,2]. The USPI is a document that highlights the entire risk versus benefit profile of a medication and serves as a reference for healthcare providers (HCPs). The package insert is a similar document that is used by pharmacy staff. A medication that has a set dosing regimen can utilize a dose pack design to ensure that the correct regimen is followed by the patient, therefore minimizing dosing errors. Finally, the labeling of a medication can display important information such as whether the medication can be addictive. These pieces are often layered together to create a cohesive approach for risk minimization. However, for drugs that carry enhanced risks due to serious safety concerns, routine risk minimization measures may be considered insufficient. In those cases, additional risk minimization measures (aRMMs) are necessary to ensure that the benefits of these products outweigh their risks [1].

Risk Evaluation and Mitigation Strategies (REMS) are required risk management plans that use risk minimization strategies beyond the professional labeling, aRMMs, to ensure that the benefits of prescription drugs outweigh their risks. The FDA Amendments Act (FDAA) of 2007 authorized the US FDA to require a REMS if the FDA determines that an REMS is necessary, especially for certain prescription drugs with serious risks [3]. REMS can be required pre-approval, or post-approval, if new safety information arises necessitating it.

REMS, additional risk minimization measures specific to USA, are designed to reinforce medication use behaviors and actions that support the safe use of those medications. REMS focus on preventing, monitoring and/or managing a specific serious risk by informing and/or reinforcing actions to reduce the frequency and/or severity of the event [4]. REMS include educational materials that provide information to HCPs and/or patients regarding risks in addition to the information in the USPI; controlled access, in which prescription or dispensing of a medicinal product is conditional on fulfilling certain criteria (e.g., following a training program or performing certain diagnostic testing); controlled distribution, in which all stages of the product distribution are tracked; and pregnancy prevention programs, which may include one or more of the measures described above [1]. Most REMS programs include a medication guide, a communication plan about the specific safety risk or risks that the REMS is intended to mitigate, elements to assure safe use, implementation system and a timetable for submission of assessments. The communication plan includes communications to patients and communications to HCPs, pharmacists, and healthcare settings. In addition to the communication component, there are REMS that have a set of other risk minimization measures collectively referred to as ‘elements to assure safe use’ (ETASU). ETASU components are designed to be undertaken before the medication can be prescribed, dispensed or received and are detailed in Table 1 [5].

While REMS is implemented by the MAH, the end users, the HCPs, are responsible for counseling patients about the REMS program. The FDA has developed a theoretical framework for HCPs to counsel patients on medications with REMS programs including the indication, dosing, efficacy and safety. According to this framework, the desired outcomes for stakeholders and healthcare systems need to be identified and then some guidance principles for counseling need to be applied; best practices for counseling about potential benefits and risks of drugs with REMS (evaluate, educate, engage and ensure) should be identified; and during the implementation phase, multiple factors need to be considered within the healthcare system such as the translation of the framework into practice and other implementation considerations (see Supplementary Figure 1) [3].

Risk management is an iterative process that is continuously applied throughout the product life cycle. New information regarding risks may become available post-authorization, requiring introduction of new aRMMs or strengthening of already existing aRMMs. Conversely, new information regarding risks post-authorization may also allow for the reduction or discontinuation of existing aRMMs [1]. In this article, we describe the framework and progress on a recently implemented REMS, the Turalio^® REMS Program.

The Turalio REMS Program

REMS rationale

Pexidartinib (Turalio; Daiichi Sankyo, Inc., NJ, USA) is a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FLT3 harboring an internal tandem duplication (ITD) mutation [6,7]. Overexpression of the CSF1R ligand promotes cell proliferation and accumulation in the synovium [7]. In vitro, pexidartinib inhibited proliferation of cell lines dependent on CSF1R and ligand-induced autophosphorylation of CSF1R. Pexidartinib also inhibited the proliferation of a CSF1R-dependent cell line in vivo [7]. Pexidartinib was approved by the FDA on 2 August 2019 for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery [8]. Pexidartinib was the first systemic therapy approved for this rare disease.

In the pivotal phase III ENLIVEN trial, the safety and efficacy of pexidartinib were compared with placebo in 120 patients with unresectable advanced TGCT [9]. Patients in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. The overall response rate was significantly higher for pexidartinib than placebo at week 25 (39 vs 0%), and the responses were durable (all 13 of responding patients who were followed for ≥12 months maintained the response) [9]. Most common adverse reactions (>20%) for pexidartinib were increased LDH, increased aspartate aminotransferase, hair color changes, fatigue, increased ALT, decreased neutrophils, increased cholesterol, increased ALP, decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia and decreased phosphate [7].

Approval of Turalio in USA was conditional on its prescription via a mandatory REMS program [8]. The REMS program was implemented due to evidence of risk of serious and potentially fatal liver injury seen in the pexidartinib clinical trials. In the ENLIVEN trial, ALT, AST, and total bilirubin elevations occurred in 67, 90 and 12% of patients, respectively, with grade ≥3 severity in a third of patients. Notably, 4.9% of patients (3 out of 61 patients; upper bound of the 95% CI: 13.7%) had laboratory abnormalities indicative of drug-induced liver injury (i.e., a total bilirubin of ≥2 × the upper limit of normal [ULN] and an AST or ALT ≥3 × the ULN) [9]. In these patients, peak ALT ranged from 6 to 9 × ULN, peak total bilirubin ranged from 2.5 to 15 × ULN, and ALP was ≥2 × ULN. ALT, AST, and total bilirubin (TBIL) improved to ULN or active liver or biliary tract disease, including increased ALP [7]. This pattern was consistent with that observed in a pooled analysis of all TGCT patients in the pexidartinib development program (n = 130) [10].

Hepatotoxicity with ductopenia and cholestasis occurred in patients treated with pexidartinib. Across 768 patients who received pexidartinib in clinical trials, there were two irreversible cases of cholestatic liver injury for non-TGCT indications (one for treatment of breast cancer and the second for unresectable or metastatic KIT-mutated melanoma). One patient died with advanced cancer and ongoing liver toxicity, and one patient required a liver transplant. The mechanism of cholestatic hepatotoxicity is unknown, and its occurrence cannot be predicted. It is unknown whether liver injury occurs in the absence of increased transaminases [7]. As a result, the prescribing information includes a Boxed Warning advising HCPs and patients about the risk of serious and potentially fatal liver injury. However, the majority of patients (2 out of 3) in the TGCT population who experienced grade ≥3 transaminase elevations and TBIL increase in the ENLIVEN trial had improvement to baseline levels with dose reductions, dose interruption and/or discontinuation of pexidartinib [9]. The clinical review team and the Division of Risk Management (DRISK) at the FDA agreed that an REMS with ETASU is needed to educate pexidartinib prescribers and further evaluate the hepatotoxicity risk outside of the clinical trial setting [8,10].

Due to the likelihood of serious and/or potentially fatal liver injury associated with pexidartinib use, the objective of the implementation of the Turalio REMS program is to mitigate the risk of serious and potentially fatal liver injury by ensuring the providers are educated on pexidartinib use and the required components of the Turalio REMS program; ensuring that prescribers adhere to requirement of baseline and periodic monitoring as described in the USPI; and enrolling all patients in a registry to further assess the safe use and acute, chronic and irreversible hepatotoxicity of pexidartinib [8]. In addition, patients are informed of this risk and agree to comply with the requirements of the REMS program.

Turalio REMS framework

The Turalio REMS program is focused on implementation of the required components of the ETASU listed in Table 1. Healthcare professionals who prescribe pexidartinib and pharmacies that dispense pexidartinib must be certified by the Turalio REMS program. Patients who receive pexidartinib must agree to enroll in the Turalio REMS program and undergo frequent liver function tests as specified by the Turalio REMS program. These requirements were implemented to ensure that prescribers and patients are educated on the potential risk of liver injury associated with pexidartinib use, and to ensure that the Turalio REMS goal of mitigating the risk of serious and potentially fatal liver injury is met.

When a patient is first diagnosed with TGCT and pexidartinib is chosen as treatment, the patient must review the Patient Guide, receive counseling about the risk of serious and potentially fatal liver injury, get the baseline liver function test, and enroll in the Turalio REMS program by completing the Patient Enrollment Form with the prescriber, all before pexidartinib treatment may begin. The details of the Patient Enrollment Form are shown in Supplementary Figure 2. The healthcare provider who prescribes pexidartinib must first become certified to prescribe, which includes reviewing the drug's prescribing information, reviewing the prescriber training, successfully completing the prescriber knowledge assessment, and enrolling in the Turalio REMS program by completing the Prescriber Enrollment Form. The details of the Prescriber Enrollment Form are shown in Supplementary Figure 3. Before the first dose is given, the prescriber must assess the patient's baseline liver function and submit the results to the Turalio REMS program through the Patient Enrollment Form.

During treatment, the patient must get weekly liver function tests for the first 8 weeks of pexidartinib treatment. The frequency decreases to every 2 weeks for 1 month following the initial 8 weeks of therapy, then decreases again to every 3 months thereafter, or more frequently based on prescriber discretion. During this time, the prescriber is continually assessing the patient's liver function and modifying the dose of pexidartinib as needed according to the Prescribing Information. As per the pexidartinib US Package Insert, if hepatotoxicity occurs during the course of pexidartinib therapy, there are a number of dose modifications and reductions that the prescriber can utilize. Dosage reductions and modifications for hepatotoxicity are described in Tables 2 and 3 [7]. Pexidartinib should be permanently discontinued in patients who are unable to tolerate 200 mg orally, twice daily.

If a liver injury occurs, an evaluation for other causes of hepatotoxicity should be conducted; the prescriber is also required to report the adverse event to the Turalio REMS program through the Liver Adverse Event Reporting Form detailed in Supplementary Figure 4.

The enrolled patient receives pexidartinib through certified pharmacies. Pharmacy certification includes designating an authorized representative to carry out the certification process and oversee the implementation and compliance with the REMS program, submitting the Pharmacy Enrollment Form detailed in Supplementary Figure 5 to the Turalio REMS program, and training all relevant staff involved with dispensing pexidartinib. Before dispensing any pexidartinib prescription, the pharmacy must obtain authorization to dispense by contacting the Turalio REMS program to verify that the prescriber is certified, and that the patient is enrolled and authorized to receive the drug. The certified pharmacy also has the responsibility to report any adverse events suggestive of serious and potentially fatal liver injury to the Turalio REMS program. When the pharmacy is dispensing pexidartinib for a new patient, for the first 3 months, they may dispense no more than a 30-day supply. Supplementary Figure 6 details the framework for the Turalio REMS program.

REMS implementation

As the marketing authorization holder, Daiichi Sankyo, Inc. (DSI) is dedicated to maintaining the Turalio REMS program. When pexidartinib was first approved in 2019, DSI disseminated targeted communication materials to HCPs likely to prescribe pexidartinib. REMS communications such as the Letter for Healthcare Providers and Letter for Professional Societies were also disseminated through various professional societies such as the Sarcoma Alliance for Research through Collaboration, the Connective Tissue Oncology Society, the American Society of Clinical Oncology and the National Comprehensive Cancer Network. The educational outreach is still ongoing in 2021, with the communication materials being disseminated at professional meetings. To support REMS operations, DSI established and maintains the Turalio REMS website, where prescribers can complete their certification and enrollment, enroll and manage their patients online, and print relevant REMS materials. Pharmacies are also able to complete their certification online through the REMS website.

The Turalio REMS program started on 2 August 2019 with United BioSource Company (UBC), an independent third party, managing certain portions of the REMS program:

• Reviewing instances of stakeholder (i.e., prescribers, pharmacies, wholesalers and distributors) non-compliance with the REMS requirements;

• Determining the course of action for recurring individual stakeholder non-compliance events;

• Tracking and monitoring non-compliance events and trends and initiating and monitoring the associated corrective and preventative actions (CAPA) for these events and trends;

• Managing REMS Compliance Committee:

  • Monitoring overall compliance metrics on an ongoing basis;

  • Working closely with stakeholders to resolve any non-compliance issues;

  • Providing an annual review of the Compliance plan.

• Ensuring compliance of individual case submissions.

Through 1 August 2021, 325 patients have been enrolled into the Turalio REMS program. Of these patients, 305 have been dispensed at least 1 prescription, for a total pexidartinib exposure of 159.31 patient-years.

The Liver Adverse Event Reporting Criteria is defined as adverse events or laboratory abnormalities suggestive of serious and potentially fatal liver injury. A patient case must meet one of the following criteria in order to be reported to the Turalio REMS program:

• ALT or AST >3 × ULN and TBIL >2 × ULN;

• ALT or AST >10 × ULN with or without TBIL elevation;

• TBIL ≥2 × ULN (or DBL >1.5 × ULN) without changes in ALT or AST;

• ALP >2 × ULN with GGT >2 × ULN;

• Liver transplantation;

• Death.

To date, 14 patients (4.6%) have met the parameters for pexidartinib discontinuation due to laboratory abnormalities suggestive of serious and potentially fatal liver injury. Thirteen patients have been discontinued from pexidartinib, and 1 of the 13 patients was restarted on pexidartinib at a reduced dose and had a negative re-challenge with no significant toxicity at last report. DSI is dedicated to obtaining accurate and appropriate follow-up for these patients to ensure that laboratory abnormalities have normalized. DSI and UBC are committed to verifying that prescribers, patients and pharmacies are compliant with the REMS program, including the pre-specified lab schedule and the dose modification guide.

Besides the Turalio REMS program, FDA requirements for pexidartinib approval included a long-term trial (PL3397-A-U401) to further evaluate the long-term risk of hepatotoxicity associated with pexidartinib use. The trial will include laboratory, imaging, and pathologic assessments of liver biopsy samples from patients who experience liver toxicity due to exposure to pexidartinib. The trial should enroll patients with AST or ALT >3 × ULN with concomitant bilirubin >2 × ULN, an isolated bilirubin >2 × ULN (excluding those with Gilbert's syndrome), or an isolated AST or ALT >10 × ULN or isolated ALP >2 × ULN with GGT >2 × ULN and with liver biopsy when liver toxicity event is reported. The trial is intended to evaluate the mechanism of action of liver injury based on liver biopsy information, including a detailed assessment of changes in resident macrophage phenotype, based on marker status, as well as detailed characterization of other immune cell infiltrates. DSI is required to submit cumulative, integrated safety analyses after 5 and 10 years of follow-up from an adequate number of patients to characterize the long-term risk of hepatic failure associated with pexidartinib use.

REMS assessment

As described earlier, risk management is an iterative process [1]. For existing REMS programs, assessments at specified time points are required by the FDA in order to determine if the REMS program is meeting its goals and whether any adjustments of the REMS components are required. These assessments are to be completed at least at 18 months, 3 years and 7 years after REMS approval. The complexity of the assessments depends on what components make up the REMS program. REMS with communication plans and/or medication guides require Knowledge, Attitude, and Behavior (KAB) surveys that measure: prescriber and patient knowledge and understanding of serious risks and safe use conditions, and/or prescriber knowledge of proper patient selection [11]. In addition to a KAB assessment, REMS with ETASU generally have additional metrics that are tracked such as data on compliance, number of enrolled/certified prescribers, number of Dear Healthcare Provider letters mailed, utilization patterns and prescribing behaviors and patient outcomes.

For Turalio REMS, the KAB assessment was administered during 8 April and 7 June 2020 via three modalities: internet, telephone and paper. The KAB survey assessed the understanding of the REMS programs across two populations, HCPs and patients. As of the data cutoff, 40 patients (including one caregiver) and 18 HCPs completed the survey. Of the 40 patients, the majority (55%) were 40–59 years of age, 70.0% were female, 70.0% were White and 73.7% had been receiving pexidartinib for 1–6 months. HCPs included were medical doctors (77.8%), advanced practice nurses (16.7%) and physician assistants (5.6%) specializing in orthopedics (4.4%: 77.8 of 5.6%) or oncology (1.2%: 22.2 of 5.6%). HCPs most commonly reported that they had practiced for 3–5 years (27.8%) or >20 years (27.8%). Almost all HCPs reported working in a hospital (44.4%), group practice (38.9%), or outpatient clinic (22.2%; respondents could select more than one type of healthcare facility). Most (72.2%) reported having prescribed pexidartinib 1–3 months (44.4%) or <1 month (27.8%) prior to participation [12].

Among patients, 87.5% demonstrated understanding of Key Risk Message 1 (KRM 1), 87.5% demonstrated understanding of KRM 2, and 77.5% demonstrated understanding of both KRMs by meeting or exceeding the 80% knowledge threshold. Among HCPs, 83.3% demonstrated understanding of KRM 1, 88.9% demonstrated understanding of KRM 2, 100% demonstrated understanding of KRM 3, and 83.3% demonstrated understanding of all 3 KRMs. KRMs are described in Table 4 [12].

The Turalio KAB survey demonstrated that both patients prescribed pexidartinib and HCPs prescribing pexidartinib to patients with TGCT have a good understanding of the KRMs, indicating that the Turalio REMS educational goal is effective. The knowledge acquisition is expected to support the REMS in the mitigation of the risk of serious and potentially fatal liver injury by ensuring that patients and HCPs are informed about the risks associated with the use of pexidartinib and the requirement for baseline and periodic monitoring during treatment.

Expert commentary & real-world practice experience

The following section describes expert opinion and clinical practice experience of VL Keedy who is an Associate Professor of Medicine in the Division of Hematology/Oncology at the Vanderbilt-Ingram Cancer Center. VL Keedy is the Clinical Director for Sarcoma, a member of the phase I Clinical Trial team, and serves as the principal investigator on several soft tissue sarcoma, bone sarcoma, GIST and phase I clinical trials. She is a member of the Sarcoma Alliance for Research Collaboration and is a member of the AJCC Soft Tissue Sarcoma Expert Panel.

TGCT is a group of rare tumors typically arising from the synovium of joints, bursae and tendon sheaths of small or large joints. These tumors are typically non-malignant neoplasms, which can be locally aggressive [13,14]. Given the location of these tumors, if not treated, they could grow to damage surrounding structures. There are two subtypes of TGCT, localized and diffuse. TGCT growth is characterized by overexpression of CSF1 and recruitment and accumulation of CSF1R–expressing cells in the synovium. In most patients, CSF1 overexpression has been reported is a result of a somatic translocation. Formation of the tumor is thought to be a mix of autocrine and paracrine processes. CSF1 overexpression activates CSF1R in cells within the tumor, resulting in the proliferation of neoplastic cells. CSF1 may also recruit CSF1R expressing myeloid lineage cells [15,16]. Overexpression of CSF1 has also been linked to inflammation and osteochondral destruction seen in some cases of TGCT [17].

Both localized and diffuse TGCT can develop over a long period of time [14,18]. Because of the slow progressive nature of the disease, symptoms may be minimal and delay diagnosis. As the tumor mass grows and gradually expands within the intra-articular space and surrounding tissue, symptoms such as pain, stiffness, swelling and reduced range of motion (ROM) of the affected joint can become severe and result in marked functional limitation. In one study of localized TGCT, the average delay before consulting a physician was 25 months for TGCT of the finger/thumb and 19 months for TGCT of the toe [19]. For diffuse TGCT, the average delay in diagnosis is 2.9 years [20]. Without treatment, TGCT may spontaneously resolve, relapse, and recur with a lifetime recurrence rate of 15% for localized type disease and up to 55% for diffuse TGCT [19]. Characteristics of TGCT subtypes are described in Table 5 [13,14,18–27].

The current treatment landscape for TCGT is very limited. Before the approval of pexidartinib, there were no FDA-approved systemic therapies available for patients with TGCT. Surgery was the only option. TGCT is a challenging disease to manage surgically. The current standard of care is surgical resection of the tumor as completely as possible in order to reduce pain, stiffness and joint destruction caused by the disease process, improve function and minimize the risk of recurrence.

Patient outcome following surgery depends on multiple factors, including the location and extent of disease and the technical skill of the surgeon. The overall recurrence rate for patients with focal localized disease is low, ranging from 0 to 6%; however, in patients with diffuse forms of the disease, recurrence is considerably more common and is estimated to be above 50%. Diffuse disease carries a risk of multiple recurrences, and affected patients often have more extensive involvement and a poorer likelihood of success with surgery. Surgical resection may involve removal of major tendons, neurovascular structures, or limbs, leading to significant postsurgical morbidity [28].

Recurrence following surgery has been a consistent problem in patients with localized TGCT and varies from 0 to 44% [28–30] (4–6% in patients with localized and 14–40% in diffuse TGCT affecting the knee at a mean follow-up of 108 months) [31]. The time from surgical excision to recurrence varies in the literature from 3 to 144 months, with most of the cases recurring within 12 to 24 months [29]. Incomplete synovectomy has been associated with 44 to 55% of recurrences [32]. In addition, delayed diagnosis is a crucial risk factor for recurrence and poor prognosis. Research has shown that two-thirds of local recurrence were diagnosed during the first 2 years and <10% after 3 years, and follow-up MRI every 6 months during the first 3 years might be able to detect >90% of all local recurrences [32]. Many factors are considered as causing recurrence of localized TGCT, including proximity to the distal interphalangeal joints, presence of degenerative joint disease, pressure erosions in the radiographs, increased mitotic activity, and type 2 lesions as described by Al-Qattan [33,34]. Cytogenetic abnormality in the form of trisomy 7 and inhibited expression of the nm23 gene is also reported to be associated with increased recurrence. Grover et al. (1998) [35] reported an inhibited nm23 gene expression in 10 (21%) of 52 tumors and this was associated with significantly increased risk of recurrence [29].

The approval of pexidartinib has opened new avenues of treatment in treating TGCT patients. For the first time, patients have another treatment option available aside from surgery. In the ENLIVEN trial, 38% of the patients on pexidartinib had at least a 30% decrease in tumor size at 24 weeks. After 25 weeks, 62% of the patients taking pexidartinib had at least a 30% decrease in tumor size (median follow-up: 38 months). At 25 weeks, pexidartinib also significantly improved the range of motion for affected joints compared with placebo [9].

All treatments are inherently associated with some risks. For pexidartinib, one of the major risks to be mitigated is hepatotoxicity. The Turalio REMS program is designed to minimize the potential risks associated with the use of pexidartinib to treat TGCT patients. Through the implementation of the REMS program, the benefits of treating patients with pexidartinib may be preserved. Overall, pexidartinib offers a unique treatment choice to improve the quality of life in TGCT patients.

At any given time, approximately 10–14 medications with an oncology indication have a REMS program; thus, many practices have developed methods to ensure compliance with multiple programs. However, in more recent years, nearly all of the oncology REMS programs have indications in malignant hematologic cancers. As a solid tumor sarcoma specialist who chose to stop using erythropoietic agents and thus never participated in their REMS programs, adapting to the requirements of the reporting system took some coordinated efforts with clinic staff and leadership.

Becoming a certified prescriber for pexidartinib entails reviewing the REMS program requirements and a relatively brief provider training slide deck, completing a Knowledge Assessment quiz and registering the provider and limited staff on the Turalio REMS website. The Turalio REMS program provides a representative to help onboard clinic staff, such as nurses, pharmacists and advanced practice providers who support the physician in the reporting steps.

Initiating a patient on treatment does have several steps, including completing and faxing a paper enrollment form that includes the patient consent. Alternatively, these steps can be completed online, but the patient is still required to sign consent. Pexidartinib is supplied by limited approved pharmacies; however, the overall approach is similar to any other specialty pharmacy dispensing oral chemotherapy medications.

The monitoring and dosing modifications for liver toxicity are similar to but significantly more intensive than what is indicated in the prescribing information for most other tyrosine kinase inhibitors (TKIs). Liver monitoring is required weekly for the first 8 weeks, every 2 weeks for weeks 9 to 12, and then every 3 months, while Patient Status Forms are required monthly for 12 weeks, every 3 months through year 1 and then every 6 months. The REMS site makes online reporting of adverse events relatively simple; the Patient Status Forms remain as PDFs that must be completed and faxed each time. While the Turalio REMS program provides reminders, keeping track of where each patient is in their treatment course, when labs are due, receiving lab results (many performed locally by outside labs), and when the status form is due for each patient can be somewhat arduous and time intensive for clinical support staff.

Prior to the FDA approval of pexidartinib for the treatment of TGCT, treatment for patients with the disease were typically managed through local modalities, with many patients requiring an open approach to obtain a macroscopically complete resection. Despite aggressive surgical approaches, patients with diffuse TGCT suffer a high rate of local recurrence, the need for repeated surgeries, and high levels of morbidity due to chronic pain and impaired range of motion. Indeed, some patients with multiple recurrences require joint replacements or even amputation. Although perioperative radiation seems to reduce local recurrence rates, this comes with a high price of radiation fibrosis, necrosis and risk of secondary sarcomas, which in general would be considered unacceptable for a benign neoplasm.

In my early career as a sarcoma medical oncologist, I only rarely saw patients with TGCT. These were typically patients presenting as described above. They had already had multiple surgeries, sometimes joint replacements, with severe bone erosions and arthritis, and were trying to avoid radiation or amputation. At that time our systemic options were limited to phase I clinical trials or off-label use of available TKIs, primarily imatinib. The link between CSF1 and TGCT was first reported around 2006 [15], not long after the first report that the M-CSF receptor c-fms (CSF1R) is a target of imatinib [36]. Subsequently, case reports and small retrospective series suggested inhibiting CSF1R was a rational approach for TGCT with high rates of symptomatic improvement; however, reported Response Evaluation Criteria in Solid Tumors (RECIST) response rates were <20% [37].

Since FDA approval of pexidartinib, patients are now referred to medical oncology far earlier in their disease course, typically at their first recurrence, if being managed at a specialty center. For patients who benefit from pexidartinib, symptom improvement is almost immediate. Patients experience improvement in pain, effusions, and joint stiffness, although patients can have ongoing regression past 12 months on treatment [38]. As patients are treated earlier in their disease course (66 and 30% received ≥2 prior surgeries in the phase I and phase III trials, respectively), they may experience even greater clinical benefit as they may have less extensive bone erosion and arthritis.

As a medical oncologist, the side effects seen in the pexidartinib clinical trials were not surprising. Fatigue, gastrointestinal symptoms, hair/skin changes and hepatotoxicity are commonly associated with TKI use, with variable rates and severity across the class. Regarding hepatotoxicity, the subject of the Turalio REMS program, the FDA has issued a Black Box Warning for at least seven TKIs for fatal hepatic failure. Monitoring for side effects, particularly liver toxicity, is an important aspect of managing all patients on TKIs and is a vital role of the medical oncologist and their staff. Having said that, it is important to track real-world data about potentially lethal toxicities in patients with a non-lethal disease, and ensure providers who may not use this class of medications routinely are well-versed in the potential toxicities and monitoring required.

Future perspective

The concept of REMS has been continually assessed and refined by the FDA since inception due to the many challenges faced by sponsors as well as the end-users in REMS implementation and assessment. There has long been discussion regarding the standardization of REMS processes due to the high degree of variability seen in the implementation and assessment of REMS programs. Sponsors implementing REMS programs that require additional components such as ETASU have the onus of creating a program that will minimize the impact on prescribers and patients while simultaneously ensuring that patient access to the drug is not unduly burdensome.

In recent years, healthcare stakeholders in various settings have successfully implemented REMS. However, stakeholders are not uniformly affected by REMS requirements. The degree to which these stakeholders are affected depends on several factors such as, organization or institution size and mission, different knowledge requirements, perceived burdens of REMS, and the nature and variations of the patient populations being served [39]. Improvement in these domains is expected in the near future with increased transparency and clear guidance and expectations from FDA.

Currently, many of the REMS assessment metrics focus on processes and not outcomes. Proxy process measures, such as KAB survey findings, have often been used to help determine if certain REMS goals have been met, but determining and collecting valid proxy process measures is challenging. Outcome-related REMS assessment metrics are challenging to collect because there are usually no pre-REMS data or other good comparator data. Furthermore, outcomes assessed are often rare events and data on drug utilization may be limited [11].

In the next few years, REMS assessments might benefit from leveraging of additional data sources (e.g., electronic health records, healthcare claims data, registry data, data from patient web-based communities) [11,39]. There is a need for FDA to assess programs earlier, more frequently and provide feedback throughout the REMS duration and apply information learned from these assessments to modify the REMS as needed [39]. In addition, as the drug and REMS programs mature with time and further evidence is collected, clear guidance is needed from FDA regarding the evidence required to modify or release a REMS and still ensure the safe use of a drug [11].

Design, implementation, management and assessment of REMS is conducted by various departments in the industry, such as pharmacovigilance, drug safety, regulatory affairs, commercial and epidemiology. Each function contributes to the success of these programs with their unique set of skills and expertise. Although responsible individuals may have specific talent, training and experience to contribute toward specific parts of REMS, they may not have training and experience in managing the entire program and the complex processes involved. In addition, REMS associates must remain up to date with changes in regulatory actions, perspectives and REMS best practices and engage in proactive dialogue with regulatory authorities in this rapidly changing field. A structured training program can provide the talent required to meet this need.

REMS are an integral element of FDA's mission to ensure the safety of drugs and biological products. FDA remains committed to systematic evaluation and improvement of REMS design, implementation, and assessment while incorporating feedback from the stakeholders and the industry to assure that patients continue to have access to safe and effective therapies.